Glucokinase (sometimes to be abbreviated to as GK in the present specification) (EC2.7.1.1) is one of the four kinds of hexokinases found in mammals, and is also called hexokinase IV. GK is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate, which is the first step of glycolysis. GK is mainly present in the pancreatic β cell and the liver, and acts in the pancreatic β cell as a sensor of extracellular glucose concentration that defines the glucose-stimulated insulin secretion. In the liver, the enzyme reaction of GK becomes a rate determining factor and regulates glycogen synthesis and glycolysis. The three hexokinases (I, II, III) other than GK reach the maximum enzyme activity at a glucose concentration of 1 mM or below. In contrast, GK shows low affinity for glucose and has a Km value of 8-15 mM which is close to a physiological blood glucose level. Accordingly, GK-mediated promotion of intracellular glucose metabolism occurs, which corresponds to blood glucose changes from normal blood glucose (5 mM) to postprandial hyperglycemia (10-15 mM).
The hypothesis proposed by Matschinsky et al. in 1984 that GK acts as a glucose sensor in the pancreatic β cell and hepatocytes has been demonstrated by the analysis of glucokinase gene manipulation mouse in recent years (see non-patent references 1-5). That is, GK heterozygous knockout mouse, showed a hyperglycemic condition, and further, a disordered glucose-stimulated insulin secretion response. GK homozygous knockout mouse dies shortly after birth with manifestations of marked hyperglycemia and urinary sugar. On the other hand, GK overexpressed mouse (hetero type) showed decreased blood glucose level, increased blood glucose clearance rate, increased liver glycogen content and the like. From these findings, it has been clarified that GK plays an important role in the systemic glucose homeostasis. In other words, decreased GK activity causes insulin secretion failure and lower liver glucose metabolism, which develops impaired glucose tolerance and diabetes. Conversely, GK activation or increased GK activity due to overexpression causes promoted insulin secretion and promoted liver glucose metabolism, which in turn increases the systemic use of glucose to improve glucose tolerance.
In addition, it has been clarified from the analysis of a report on GK gene abnormality mainly in the family of MODY2 (Maturity Onset Diabetes of the Young) that GK also acts as a glucose sensor in human, and plays a key role in glucose homeostasis (see non-patent reference 6). In GK gene abnormality, due to the decreased affinity of GK for glucose (increased Km value) and decreased Vmax, the blood glucose threshold value of insulin secretion increases and the insulin secretory capacity decreases. In the liver, due to the decreased GK activity, decreased glucose uptake, promoted gluconeogenesis, decreased glycogen synthesis and liver insulin resistance are observed. On the other hand, a family with a mutation increasing the GK activity has also been found. In such family, fasting hypoglycemia associated with increased plasma insulin concentration is observed (see non-patent reference 7).
As mentioned above, GK acts as a glucose sensor in mammals including human, and plays an important role in blood glucose regulation. On the other hand, control of blood glucose utilizing the glucose sensor system of GK is considered to open a new way to treat diabetes in many type 2 diabetes patients. Particularly, since a GK activating substance is expected to show insulin secretagogue action in the pancreatic β cell and glucose uptake promotive action and glucose release suppressive action in the liver, it will be useful as a prophylactic or therapeutic drug for type 2 diabetes.
In recent years, it has been clarified that pancreatic β cell type glucokinase expresses locally in the feeding center (Ventromedial Hypothalamus: VMH) of rat brain. A subset of nerve cell present in VMH is called glucose responsive neuron, and plays an important role in the body weight control. From electrophysiological experiments, the neuron is activated in response to physiological changes in the glucose concentration (5-20 mM). However, since the glucose concentration sensor system of VHM is assumed to have a mechanism mediated by glucokinase as in the case of insulin secretion in the pancreatic β cell, separately from pancreatic β cell and the liver, a pharmaceutical agent capable of activating glucokinase of VHM has a possibility of providing not only a blood glucose corrective effect but also improvement of obesity.
As mentioned above, a GK activator is useful as a prophylactic or therapeutic drug for diabetes and diabetic complications, and further, as a prophylactic or therapeutic drug for obesity.
As a fused pyrrole compound, the following compounds have been reported.    (1) A compound represented by the formula:
wherein    Y is O or S; P is an alkyl group, an aryl group or a benzyl group; and R8 and R9 are each independently —H, —F, a C1-4 alkyl group, a C1-4 alkoxy group, —[NRt]SO2—C1-4 alkyl wherein Rt is —H, a C1-4 alkyl group and the like has been reported as an synthetic intermediate for a therapeutic drug for histamine H4 receptor-mediated diseases (see patent document 1).    (2) A compound represented by the formula:
wherein Q is a phenyl group; Z and X are each independently C, CH, CH2, N, O or S; each — is a bond or absent (provided that — is not a bond at the same time); R1 is a hydrogen atom or a halogen atom; each of Ra and Rb is independently a hydrogen atom or —C1-8 alkyl; Y is —CH(OH)— or absent; R2 is a hydrogen atom, a halogen atom, —C1-8 alkyl and the like; R3 is a hydrogen atom, a halogen atom, —C1-8 alkyl, —O—C1-8 alkyl, —NH—C1-8 alkyl and the like; R4 is —C(═O)A; A is —NRdRd or
each Rd is independently a hydrogen atom, —C1-8 alkyl, —C1-8 alkoxy and the like; X1 is —NRa, —CH2—, O or S; each Rc is independently a hydrogen atom, —C(═O)ORa, —ORa, —SRa or —NRaRa; and n is independently 1 to 3 has been reported as a glycogen phosphorylase inhibitor, and a compound represented by the formula
wherein R′ and R′″ are each independently a hydrogen atom or halide, and other symbols are as defined above, has been reported as a synthetic intermediate therefor (see patent documents 2, 3 and 4).    (3) The following compounds have been reported as angiotensin II antagonists (see non-patent document 8):    methyl 3-{[2′-(methoxycarbonyl)biphenyl-4-yl]methyl}-2-propyl-3,4-dihydropyrrolo[2,3-d]imidazol-5-carboxylate
    methyl 2-butyl-3-{([2′-(methoxycarbonyl)biphenyl-4-yl]methyl}-3,4-dihydropyrrolo[2,3-d]imidazol-5-carboxylate
    4′-{[5-(methoxycarbonyl)-2-propylpyrrolo[2,3-d]imidazol-3(4H)-yl]methyl}biphenyl-2-carboxylic acid
and    4′-{[2-butyl-5-(methoxycarbonyl)pyrrolo[2,3-d]imidazol-3(4H)-yl]methyl}biphenyl-2-carboxylic acid
    (4) The following compounds have been reported as therapeutic drugs for hypertension (see non-patent document 9):    ethyl 3-[4-(ethoxycarbonyl)benzyl]-2-propyl-3,4-dihydropyrrolo[2,3-d]imidazol-5-carboxylate
and    ethyl 2-butyl-3-[4-(ethoxycarbonyl)benzyl]-3,4-dihydropyrrolo[2,3-d]imidazol-5-carboxylate
    (5) A compound represented by the formula:
wherein A and B in combination form an optionally substituted 5-membered aromatic ring (containing one or more hetero atoms); R27 is —H, —COOH, —C(O)CH2OH, —CONHR4 and the like wherein R4 is —H, an alkyl group and the like; and R3 is —H and the like, specifically, ethyl 3-methyl-3,4-dihydropyrrolo[2,3-d]imidazol-5-carboxylate
has been reported as a synthetic intermediate for an anti-inflammatory compound (see patent document 5).    (6) The following two compounds have been reported as intermediates for synthesizing porphyrins (see non-patent document 10):    ethyl 3,6-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-carboxylate
and    benzyl 6-(acetoxy)-3-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrol-2-carboxylate
    (7) A compound represented by the formula:
wherein one of U and V is —S— and the other is —C(R3)—; one of R2 and R3 is -D-E (D is a bond, —O—, —CH2— and the like; E is an aryl group and the like) and the other is a hydrogen atom, a halogen atom and the like; R4 is —OR12a or —N(R12b)R13b; R12a, R12b and R13b are each independently a hydrogen atom, an aryl group, a C1-8 alkyl group and the like; and X1 is a hydrogen atom, a halogen atom and the like, has been reported as a synthetic intermediate for a therapeutic agent for inflammation (see patent document 6).    (8) A compound represented by the formula:
has been reported as an intermediate for synthesizing roseophilin (see non-patent document 11).
However, none of the references discloses that a compound represented by the following formula (I) has a glucokinase activating action.    patent document 1: WO 2004/022537    patent document 2: EP-A-1088824    patent document 3: EP-A-1391460    patent document 4: EP-A-1136071    patent document 5: WO 99/40914    patent document 6: WO 2006/077412    non-patent document 1: J. Biol. Chem., 1995, vol. 270, pages 30253-30256    non-patent document 2: J. Biol. Chem., 1997, vol. 272, pages 22564-22569    non-patent document 3: J. Biol. Chem., 1997, vol. 272, pages 22570-22575    non-patent document 4:Nippon Rinsho, 2002, vol. 60, pages 523-534    non-patent document 5: Cell, 1995, vol. 83, pages 69-78    non-patent document 6: Nature, 1992, vol. 356, pages 721-722    non-patent document 7: New England Journal Medicine, 1998, vol. 338, pages 226-230    non-patent document 8: IL FARMACO, 2003, vol. 58, pages 1193-1199    non-patent document 9: Indian Journal of Chemistry, 1997, vol. 36-B, pages 813-815    non-patent document 10: J. Heterocyclic Chem, 1993, vol. 30, pages 447-482    non-patent document 11: Tetrahedron Letters, 1999, vol. 40, pages 6117-6120